Genetics Commons^™

Transcriptional Regulation In The Uterine Luminal Epithelium, Evelyn A. Carrion

Dissertations and Theses (Open Access)

Transcriptional Regulation in the Uterine Luminal Epithelium

Evelyn A. Carrion

Advisor: Richard R. Behringer, PhD

Abstract

The uterus is an organ comprised of multiple tissues that are essential for women’s health and reproduction. The uterus is composed of multiple tissue layers, including the perimetrium, myometrium, and the endometrium. The endometrium is the inner lining of the uterus, and contains the luminal epithelium, glandular epithelium, and stroma. The luminal epithelium is a simple columnar layer of cells that is necessary for embryo implantation. The uterus is derived in part from the embryonic precursor tissue called the Müllerian duct. There are no …

Regulation Of Müllerian Duct Mesenchyme Transcription During Mammalian Sex Differentiation, Haowen Li, Richard R Behringer, Rachel D Mullen

Dissertations and Theses (Open Access)

Sp7/Osterix (Osx) encodes a zinc-finger transcription factor of the Specificity-protein family discovered by Nakashima et al. at the MD Anderson Cancer Center. While primarily recognized for its role in osteogenesis, Osx has also been implicated in mammalian reproductive development, particularly in male sex differentiation, where Müllerian Duct (MD) regression occurs, mediated by anti-Müllerian hormone (AMH) signaling. AMH-induced regression signals are transduced by the mesenchymal tissue surrounding the ductal structure, known as the Müllerian Duct mesenchyme (MDM). It was discovered that AMH signaling is necessary and sufficient for driving Osx expression in MDM. A previous transgenic mouse reporter …

Mutational Analysis Of Domain Functions In The Yeast Decapping Enzyme Dcp2, Jellisa Ewan, Ambro Van Hoof

Dissertations and Theses (Open Access)

In yeast, the major mRNA decay pathway involves deadenylation of the 3’ poly-A tail, followed by decapping of the 5’ m7Gppp cap and subsequent 5’ to 3’ degradation or 3’ to 5’ degradation. This is carried out by Pan2/Pan3 and Ccr4/Not deadenylases, the decapping enzyme Dcp2, and Xrn1 and  RNA exosome exoribonucleases, respectively. The eukaryotic mRNA decapping enzyme complex, Dcp1/Dcp2, is essential in yeast, and deletion of either gene is lethal. However, the deadenylases that act upstream and the 5’ exoribonuclease that act downstream of the decapping step are not, even though they are all highly conserved with no known …

Context Dependent Regulation Of Dicer Function During Oocyte-To-Embryo Transition, Nick A. Newkirk

Dissertations and Theses (Open Access)

Over two decades ago, Dicer was discovered as the primary enzyme responsible for the generation of small RNAs known as the microRNAs (miRNAs) and short interfering RNAs (siRNAs). Spatiotemporal regulation of Dicer-dependent small-RNA biogenesis affects many aspects of biology, including aging, disease progression, fertility, and cancer. Interestingly, a distinct population of Dicer-dependent small RNAs, known as the endogenous siRNAs (endo-siRNAs), are uniquely abundant in the germ cells and gametes, and are critical for normal fertility. Despite their function regulating new life, the mechanisms controlling their biogenesis and subsequent germ cell functions remain poorly defined. Work to parse these mechanisms in …

The Role Of Cleavage And Polyadenylation Spcific Factor 6 (Cpsf6) In Hematopoiesis, Fengxi Ye

Dissertations and Theses (Open Access)

Cleavage and polyadenylation specific factor 6 (Cpsf6) translocation is frequently reported in APLL, which is Acute Promyelocytic Leukemia (APL)-like acute myeloid leukemia (AML) and other types of blood diseases associated with abnormal hematopoiesis. CPSF6 is a subunit of the Cleavage Factor I mammalian (CFIm) complex, which regulates post-transcriptional alternative polyadenylation (APA) of pre-mRNAs. Previous research indicated that Cpsf6 plays an essential role in alternative polyadenylation, development, and tumorigenesis. However, the role of Cpsf6 in hematopoiesis is unknown. Given its roles in APA, development and cancer, we hypothesize that Cpsf6 plays a critical role in hematopoiesis and that its …

Investigating The Role Of The Lysine-Specific Demethylase 4c In Pancreatic Ductal Adenocarcinoma, Mennatallah Shaheen

Dissertations and Theses (Open Access)

Deregulation of proteins involved in chromatin regulation is common in pancreatic ductal adenocarcinoma (PDAC). Lysine demethylase 4C (KDM4C) is one of the chromatin modifying proteins frequently overexpressed across multiple solid cancers and is linked to chromatin instability, increased cell proliferation, and enhanced stem cell-like behavior. We observed upregulation of KDM4C protein in a panel of human PDAC cell lines and patient samples compared to non-neoplastic controls. CRISPR/Cas9-mediated deletion of KDM4C in human and murine PDAC cells reduced proliferation, clonogenicity, and increased survival of orthotopically implanted murine PDAC allografts. Transcriptomic and proteomics analyses revealed that loss of KDM4C in both human …

Evaluating Cancer Rates, Cancer Types, And Variant Hotspots Between Different Races And Ethnicities In Individuals With Li-Fraumeni Syndrome, Hillary Esplen

Dissertations and Theses (Open Access)

Li Fraumeni Syndrome (LFS) is a cancer predisposition syndrome that increases the risk for numerous cancer types in both children and adults. In the general population, incidence rates for various cancer types differ among races and ethnicities. Although a few germline TP53 pathogenic/likely pathogenic (P/LP) variants in those with LFS have been studied and associated with specific populations, such as the South and Southeast Brazil founder variant, p.Arg337His, there still lacks research on the variable expressivity of cancers within the LFS population based on specific variant, race and/or ethnicity. This study aims to describe the specific TP53 germline variants, the …

Elucidating The Multi-Omics Of Early-Onset Colorectal Cancer, Jumanah Alshenaifi

Dissertations and Theses (Open Access)

The incidence and mortality rates of sporadic early-onset colorectal cancer have increased in recent decades, but there is no clear etiological basis for this trend. EOCRC is commonly defined as colon and rectal cancers diagnosed before the age of 50 years. The rising incidence of EOCRC has made it the second most common cancer and the third leading cause of cancer death in this age group. The rising incidence of EOCRC is also documented internationally in more than 20 countries across different continents. Clinically, EOCRC has a distinct, more aggressive clinical profile than LOCRC. While approximately 15% of EOCRC cases …

The Influence Of Scientific, Genetic, And Health Literacy On Carrier Screening Decision-Making, Brenna D. Albracht

Dissertations and Theses (Open Access)

For those wishing to assess their reproductive risks and make informed decisions in their reproductive planning, carrier screening for autosomal recessive and X-linked conditions, as well as cell-free DNA (cfDNA) screening for aneuploidy, are recommended during pregnancy. Despite similarities in purpose, sample requirements, insurance coverage, and safety, a lower percentage of individuals elect carrier screening than cfDNA screening, suggesting there may be a disconnect in what patients perceive as valuable information for their pregnancy. Previous studies have attempted to explain the factors associated with carrier screening uptake or decline; however, no models have yet accounted for a patient’s literacy level …

"Magic Computer In The Sky" - Participant Perspectives On Control And The Genetic Counseling Admissions Match, Jessica Clark

Dissertations and Theses (Open Access)

Since the 2018 admissions cycle, genetic counseling graduate programs in North America have utilized the Genetic Counseling Admissions Match (GCAM), a Match algorithm to place applicants. While a study prior to implementation found that most students were uninterested in a Match due to concerns of control, there has been no investigation into matched applicants’ experiences since its inception. A mixed-methods study explored the experiences and perceptions of control of genetic counselors and genetic counseling (GC) students who entered a program following the GCAM. An anonymous survey documenting GCAM experience and a validated measure for locus of control (LOC) was disseminated …

Evaluating Triage To Genetic Counseling Using An Online Reproductive Genetics Module, Grace Ra

Dissertations and Theses (Open Access)

The American College of Obstetricians and Gynecologists recommends genetic screening for all pregnant women. As clinical recommendations broaden and demand for prenatal screening increases, obstetric practitioners report time constraints and lack of genetics knowledge as challenges to providing sufficient pretest education. These challenges in offering routine screening are further compounded by the inequities in access to genetic counseling and testing. Thus, alternative education and service delivery models have emerged to meet the demands for prenatal genetics education and help mitigate challenges surrounding access. At UTHealth Houston, an online triage and education module, the Prenatal Genetics Education Program (PGEP), was created …

The Role Of Wt1 In Müllerian Duct Development, Jace Aloway

Dissertations and Theses (Open Access)

WT1 is a zinc finger transcription factor widely expressed in the urogenital system. Human mutations of WT1 lead to pediatric nephroblastoma as well as frequent differences of sex development (DSDs). Previous studies have suggested that WT1 acts as an activator for Amhr2, a necessary component of typical male differentiation. We used the mouse as a model to investigate the role of WT1 in sex development, where we deleted Wt1 in the Müllerian duct (MD) mesenchyme using a novel conditional null reporter allele, Wt1 flox-RFP. This allele utilizes the Cre-lox system to delete exons 8 and 9 of Wt1 …

Assessing The Temporal Role Of Mir-200 Loss In Murine Models Of Nsclc, Jared Fradette

Dissertations and Theses (Open Access)

Lung cancer is the leading cause of cancer related deaths in the United States, with non-small cell lung cancer (NSCLC) making up a majority of new diagnoses. Metastasis is the big killer in NSCLC and is driven by epithelial-mesenchymal transition (EMT) and immune evasion. The microRNA 200 family is a master regulator of EMT and is implicated in immune regulation. In this study we have developed a novel genetically engineered mouse model (GEMM) and derived primary cell lines from them to explore the role of microRNA-200 in early EMT and immune changes. Our model combines conditional activation of Kras^{G12D …}

Early Onset Alzheimer’S Disease Markers In Mouse Hippocampus Unveiled By Single-Cell Transcriptomic Analysis Following Cranial Radiotherapy, Tuba Aksoy

Dissertations and Theses (Open Access)

Cranial radiation therapy plays an integral role in the treatment of brain tumors but can lead to progressive cognitive deficits in survivors by mechanisms that are poorly understood. To develop preventive or mitigative strategies, it is crucial to better understand the underlying pathogenesis of radiation-induced cognitive impairments. The study investigated single-cell transcriptomics and DNA methylation changes as potential drivers of persistent cellular dysfunction after radiation exposure, specifically concentrating on the CA1-3 regions of the hippocampus and the prefrontal cortex due to their role in cognitive functions. Thirteen-week-old mice underwent whole-brain radiation at clinically relevant doses. Following whole-brain radiation, an assessment …

Utilizing The In4mer Crispr/Cas12a Multiplex Knockout Platform To Investigate Synthetic Lethality In The Human Genome, Xingdi Ma

Dissertations and Theses (Open Access)

The emergence of high-throughput sequencing technologies and the development of targeted cancer therapies have significantly advanced our understanding of cancer genomics and prolonged patient survival. Despite these advances, durable response remains difficult to achieve in the clinic. The concept of synthetic lethality has gained traction as a promising opportunity to discover novel cancer-specific vulnerabilities and therapeutic targets. Unfortunately, initial technologies for combinatorial genetic perturbation in mammalian cells suffer from inefficiency and are challenging to scale. In this dissertation, I report: 1) paralog selection method to select candidate synthetic lethal paralogs; 2) our Cas12a multiplex platform “IN4MER” that provides superior sensitivity …

The Role Of The Transcription Factor Cebpa In Regulating Lung Alveolar Type 2 Cell Fate In Vivo, Dalia Hassan

Dissertations and Theses (Open Access)

Cell plasticity can extend across all possible cell types, yet it naturally diminishes as cells progress through differentiation. This plasticity can be reactivated during injury repair, engaging developmental flexibility. Our investigations reveal the critical role of the transcription factor (TF) CEBPA, specific to lung alveolar type 2 (AT2) cells, in modulating AT2 cell plasticity within the mouse lung. We demonstrate that CEBPA constrains AT2 cell plasticity by promoting the AT2 differentiation program and recruiting the lineage-specific TF NKX2-1. Without CEBPA, AT2 cells, in both neonatal and mature, show a diminished AT2 program; however, only neonatal cells re-activate the SOX9 progenitor …

Mismatch Repair Deficient Neoantigen And Associated Circulating T-Cell Receptor Repertoires In Lynch Syndrome, Ana Bolivar

Dissertations and Theses (Open Access)

Lynch Syndrome (LS) is the most common inherited colorectal cancer (CRC) syndrome. It constitutes the perfect model to understand DNA mismatch repair deficient (MMRd) carcinogenesis, which underlies 15% of early-stage CRC. LS patients develop MMRd tumors with high loads of shared neoantigens (neoAgs), which are recognized by the immune system. Previous research has concentrated on discovering neoAgs and their potential as targets for vaccines in LS patients. However, these studies have primarily identified shared neoAgs from cancers, lacking detailed information on targetable neoAgs present in precancerous lesions. Understanding this landscape of pre-cancer derived neoAgs is crucial for intercepting cancer development …

Uncovering Capillary Endothelial Cells Response During Lung Injury-Repair, Celine Shuet Lin Kong

Dissertations and Theses (Open Access)

Once thought to be a homogenous population, capillary endothelial cells (ECs) have embodied organotypic specialization and heterogenous properties, both during homeostasis and tissue injury. In the lung, capillary ECs consist of two distinct populations, CAP1 and CAP2s; how each population responds to diverse tissue injury is incompletely understood. In this thesis, I report the induction and function of a truncated isoform of Ntrk2, Ntrk2^-tk (lacking the tyrosine kinase domain) in multiple injury models. Using a combinatorial approach of single-cell multiome, mouse genetics and viral infection models, I found that Ntrk2^-tk is broadly induced in CAP1s after the initial …

Epigenetic Modification As A Therapeutic Target In Brafv600e-Mutated Metastatic Colorectal Cancer, Hey Min Lee

Dissertations and Theses (Open Access)

Patients with BRAF^V600E-mutated metastatic colorectal cancer (mCRC) experience a worse prognosis and demonstrate only a 5% response rate to BRAF inhibitor treatment. In this study, adaptive resistance, and a potential combination of standard therapies in BRAF^V600E CRC were unveiled. Intriguingly, a robust association of BRAF^V600E mutation and DNA hypermethylation suggests this is a unique subgroup harboring aberrant epigenetic phenotype. Firstly, DNA methyltransferase (DNMT) inhibitor treatment induced profound DNA hypomethylation in vivo, but minimal change in gene expression due to adaptive elevation of the repressive histone methylation, H3K27me3, leading to compensatory suppression of key tumor suppressor genes, …

Patient Preferences For Ultrasound Soft Sign Disclosure With Prior Negative Cfdna Screening, Disha Patel

Dissertations and Theses (Open Access)

Soft signs are nonstructural fetal anomalies that can be identified by the second-trimester comprehensive ultrasound examination. In isolation, soft signs are insufficient to diagnose chromosome conditions but can adjust an individual's risk for aneuploidy, primarily Down syndrome. In the age of noninvasive cell-free DNA (cfDNA) prenatal screening, which exhibits superior sensitivity and specificity for aneuploidy compared to what can be provided by soft sign risk adjustment, the utility of these soft signs is arguably waning. Thus, this study aimed to establish patient preferences for whether and how soft signs are disclosed in pregnancy to inform recommendations for disclosure. A survey …

Acute Pain Prediction In Oral Cavity And Oropharyngeal Cancer Patients Receiving Radiation Therapy, Vivian Salama

Dissertations and Theses (Open Access)

Oral-Cavity and oropharyngeal cancers (OC/OPC) are types of head and neck cancers that are increasing in incidence domestically. Radiation therapy (RT) is crucial in OC/OPC management. Pain is a common and challenging symptom for most patients during therapy, as nearly all patients undergoing locoregional RT in OC/OPC require analgesia for acute iatrogenic pain. Moreover, about 45% of long-term survivors report chronic pain, with more than 10% exhibiting severe chronic pain. Pain control is challenging due to the multifactorial clinical, molecular, and cellular etiology of cancer/therapy pain, as well as variation in pain assessment and the non-uniform management of pain between …

Influential Factors For Disclosing A Tuberous Sclerosis Complex Diagnosis To Romantic Partners, Laura Gorecki

Dissertations and Theses (Open Access)

Tuberous sclerosis complex (TSC) is a highly variable genetic condition characterized by multi-organ tumor predisposition. Due to the heritability, variability, and severity of this condition, individuals with TSC may face unique psychosocial challenges in dating and romantic relationships, specifically related to disclosing their diagnosis to romantic partners. Despite disclosure within romantic relationships being explored in the context of other genetic conditions, this area has not yet been explored in the TSC community who face unique challenges related to physical and mental health, educational performance, and overall quality of life. This study surveyed 117 independent adults with TSC regarding the following …

Efficacy Of Genetic Testing Methodologies For Prenatal Detection Of Skeletal Anomalies And Craniosynostosis Syndromes, Nicolette Murphey

Dissertations and Theses (Open Access)

Prenatal ultrasound findings suggestive of skeletal dysplasia often have a wide differential with over 450 skeletal dysplasia syndromes described to date. Specific phenotypic features on ultrasound provide guidance, though we noted in this study that molecular testing is most informative in making a diagnosis. Prenatal genetic testing ranges from screening tests using cell-free fetal DNA to diagnostic tests which include next generation sequencing panels and whole exome or genome sequencing. We aimed to determine which prenatal genetic tests were capable of identifying disease causing variants in pregnancies suspected to have skeletal dysplasia and craniosynostosis syndromes. This multi-center retrospective chart review …

The In4mer Crispr/Cas12a Multiplex Knockout Platform And Its Applications, Nazanin Esmaeili Anvar

Dissertations and Theses (Open Access)

Discovering synthetic lethal interactions between genes holds the key to uncovering cancer vulnerabilities, enabling the development of more effective drugs for patients. However, identifying these vulnerabilities in the complex genome of human, which comprises thousands of genes, poses a significant challenge. One alternative approach to investigate these interactions involves exploring enriched sources of synthetic lethal interactions, such as paralog pairs. In recent years, a couple of studies have conducted dual-gene knockout experiments on paralog pairs using different approaches to identify synthetic lethal interactions. In this study, we conducted a meta-analysis of CRISPR genetic interaction screens. We identified a candidate set …

Dysmorphology Training And Utility In Genetic Counseling, Maria G. Hernandez

Dissertations and Theses (Open Access)

Before the availability of comprehensive genetic testing, dysmorphology was critical for developing a differential for individuals suspected of having a genetic disorder. Literature suggests that the availability of whole exome and whole genome sequencing (ES/GS) has shifted the use of dysmorphology from a forward to backward approach. There is no literature describing the continued use of dysmorphology within the genetic counseling field or the training that genetic counseling students receive. The study aims to describe the dysmorphology training that genetic counselors (GC) and GC students reported receiving, to explore the involvement of GCs in evaluating dysmorphic features and identify factors …

Inclusion Of Adoption As A Pregnancy Management Option In Prenatal Genetic Counseling Practice, Emma Billings

Dissertations and Theses (Open Access)

Prenatal genetic counselors are essential to providing education, psychosocial support, and guidance on pregnancy options to patients who receive a fetal diagnosis of an anomaly or genetic condition. Therefore, genetic counselors should be well-educated on comprehensive pregnancy management options consisting of parenting, abortion, and adoption. The landscape of adoption education in genetic counseling practice was last characterized in 2010 by Perry and Henry, revealing substantial variability in both the inclusion of adoption-specific education in genetic counseling program (GCP) curricula and the discussion of pregnancy options with patients in prenatal practice. As a result, the authors published a call to action …

Dysmorphology Training And Utility In Genetic Counseling, Maria Hernandez, Maria Hernandez

Dissertations and Theses (Open Access)

Before the availability of comprehensive genetic testing, dysmorphology was critical for developing a differential for individuals suspected of having a genetic disorder. Literature suggests that the availability of whole exome and whole genome sequencing (ES/GS) has shifted the use of dysmorphology from a forward to backward approach. There is no literature describing the continued use of dysmorphology within the genetic counseling field or the training that genetic counseling students receive. The study aims to describe the dysmorphology training that genetic counselors (GC) and GC students reported receiving, to explore the involvement of GCs in evaluating dysmorphic features and identify factors …

A Continuous Local Ancestry Measure For Efficient Local-Ancestry-Aware Association Tests, Hanxiao Sun

Dissertations and Theses (Open Access)

Genetic association tests have enabled people to identify susceptible loci and broadened our understanding of complex diseases. However, the GWAS (Genome-wide Association Studies) results are probably confounded by population stratification thus leading to potential false-positive findings. This problem is pronounced particularly in admixed populations, a group of populations with multiple ancestries whose local genetic ancestry may drastically vary at local genomic positions (local ancestry) compared to the overall genetic ancestral composition (global ancestry). It is insufficient to only account for global population structure in admixed populations. Methods have been developed to account for local population stratification but followed by subsequent …

A Study Of The Snd1/Prmt5 Axis In Liver Cancer By Genetic Mouse Models, Tanner Wright, Tanner Wright

Dissertations and Theses (Open Access)

Arginine methylation is an essential post-translational modification (PTM) in cells. Protein arginine methyltransferase 5 (PRMT5) is the primary enzyme that catalyzes symmetric dimethyl arginine (SDMA) and requires methylosome protein 50 (MEP50) for stability and enzymatic activity which are necessary for life and development. Effector proteins bind different types of PTM’s to facilitate signaling. Staphylococcal nuclease Tudor domain containing 1 (SND1) is an effector that specifically binds SDMA via its single C-terminal Tudor domain. Both SND1 and PRMT5 have been implicated in hepatocellular carcinoma (HCC). SND1 has been confirmed as a driver of HCC using genetically engineered mouse models (GEMMs), though, …

Genomic Characterization Of Adolescent And Young Adult Cancers: Investigation Of Ewing Sarcoma Susceptibility And Chornobyl Thyroid Tumors, Olivia Lee

Dissertations and Theses (Open Access)

Adolescent and young adult (AYA) cancers, diagnosed between the ages of 15 and 39, can exhibit distinctive genetic and molecular characteristics. Reported epidemiologic findings and treatment outcomes based on pediatric and adult cancer studies are often not suitable for application to the AYA population, underscoring the need for more thorough genomic research. Advances in sequencing technologies have enabled comprehensive analyses of complex genomic characteristics of AYA cancers, crucial for understanding the underlying biology of these malignancies. Here, I have utilized advanced sequencing techniques and integrated analytic approaches to describe important genomic features in two different AYA cancer types: Ewing Sarcoma …